Incorporating poly-N-vinly amide in a transdermal system

ABSTRACT

The present invention comprises a composition comprising a matrix ( 12 ) adapted to be placed in drug- and permeation-enhancing mixture-transmitting relation to a selected skin ( 18 ) or other body site. The matrix ( 12 ) contains sufficient amounts of drug, permeation enhancer(s) and poly-N-vinyl amide to continuously administer to the site, the drug, in a therapeutically effective amount, and the permeation-enhancing mixture, in an amount effective to enhance the permeation of the skin ( 18 ) to the drug, the device ( 10 ) shows increased transdermal flux as compared to the transdermal flux of the drug from a device ( 10 ) containing no poly-N-vinyl amide. Incorporating poly-N-vinyl amide into the transdermal system also improves the adhesion and stability of the system.

This application is a continuation of application Ser. No. 08/564,058filed Dec. 14, 1995, now U.S. Pat. No. 5,929,478, which is a 371 ofPCT/US94/07267 filed Jun. 24, 1994 and CIP of 08/082,624, filed Jun. 25,1993, now abandoned.

TECHNICAL FIELD

This invention relates to the transdermal delivery of drugs and otherbiologically active agents. More particularly, this invention relates tothe transdermal delivery of drugs utilizing a novel combination of apermeation enhancer and a poly-N-vinyl amide to enhance flux,wearability, or stability of a transdermal device.

BACKGROUND ART

The transdermal route of parenteral delivery of drugs provides manyadvantages over other administrative routes, and transdermal systems fordelivering a wide variety of drugs or other beneficial agents aredescribed in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494;4,031,894; 4,201,21 1; 4,286,592; 4,314,557; 4,379,454; 4,435,180;4,559,222; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062;4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610, for example.The disclosures of the above patents are incorporated herein byreference. In many instances, drugs that would appear to be idealcandidates for transdermal delivery are found to have such lowpermeability through intact skin that they cannot be delivered attherapeutically effective rates from reasonably sized systems.

In an effort to increase skin permeability, it has been proposed topretreat the skin with various chemicals or to concurrently deliver thedrug in the presence of a permeation enhancer. Various materials havebeen suggested for this purpose, as described in U.S. Pat. Nos.3,472,931, 3,527,864, 3,896,238, 3,903,256, 3,952,099, 4,046,886,4,130,643, 4,130,667, 4,299,826, 4,335,115,4,343,798, 4,379,454,4,405,616 and 4,746,515, all of which are incorporated herein byreference; British Pat. No. 1,001,949; and Idson, PercutaneousAbsorption, J. Pharm. Sci., Vol. 64, No. b6, June 1975, pp 901-924(particularly 919-921).

Many permeation enhancers interact adversely with other components oftransdermal devices. One problem is that many permeation enhancers arenot compatible with medically acceptable contact adhesives. This cancause, among other problems, cohesive failure of adhesives.Additionally, the permeation enhancers can partition into othercomponents in the system. This can cause devices to delaminate or it cancause instability of the device, thus shortening its shelf life.

Another problem related to adhesives of transdermal systems is theproblem of adhesive failure resulting in water induced fall-off of thesystem. Adhesive failure may be caused by accumulation of the permeationenhancer at the skin-adhesive interface. As water accumulates on theskin, particularly during exercise or bathing, the interaction betweenthe water and the permeation enhancer causes a soapy solution to form atthe interface thereby causing the transdermal system to fall off.

This invention utilizes a novel combination of permeation enhancer(s)and a poly-N-vinyl amide. The novel combination produces a significantand surprising improvement in transdermal fluxes, drug utilization,storage stability, and improved adhesion over previous transdermaldevices.

SUMMARY OF THE INVENTION

The present invention comprises a device for the transdermaladministration, at a therapeutically effective rate, of a drug, whichdevice comprises a reservoir comprising a therapeutically effectiveamount of drug, a skin permeation-enhancing amount of a permeationenhancer and a poly-N-vinyl amide; a backing on the skin-distal surfaceof the reservoir; and means for maintaining the reservoir in drug- andpermeation enhancer-transmitting relation with the skin.

The present invention further comprises a device for the transdermaladministration, at a therapeutically effective rate, of drug, whichdevice comprises a first reservoir comprising a therapeuticallyeffective amount of drug, a skin permeation-enhancing amount of apermeation enhancer and a poly-N-vinyl amide; a second reservoircomprising a permeation enhancer and a poly-N-vinyl amide, andoptionally containing drug; a rate-controlling membrane between thefirst reservoir and the second reservoir; a backing on the skin-distalsurface of the second reservoir; and means for maintaining the first andsecond reservoirs in drug- and permeation enhancer-transmitting relationwith the skin.

The present invention also includes a method for the transdermaladministration of a drug, the method comprising the step of placing atransdermal drug delivery device as described above onto the skin of aperson.

The present invention also includes a method for increasing thetransdermal flux of a drug from a transdermal device comprisingincorporating into the drug containing reservoir of the transdermaldevices described above, an effective amount of a poly-N-vinyl amide,wherein the device is used in the method for transdermal administrationof a drug described above.

The present invention also includes a method for improving the adhesionof a transdermal delivery device comprising incorporating into the drugcontaining reservoir of the transdermal devices described above, aneffective amount of a poly-N-vinyl amide, wherein the transdermaldelivery device is used in the method for transdermal administration ofa drug described above.

The present invention also includes a method for improving the stabilityof a transdermal delivery device comprising incorporating into the drugcontaining reservoir of the transdermal devices described above, aneffective amount of a poly-N-vinyl amide, wherein the transdermaldelivery device is used in the method for transdermal administration ofa drug described above.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in further detail with reference to theaccompanying drawings wherein:

FIG. 1 is a cross-sectional view of one embodiment of the transdermaldrug delivery system according to this invention.

FIG. 2 is a cross-sectional view of another embodiment of thetransdermal drug delivery system of this invention.

FIG. 3 is a cross-sectional view of still another embodiment of thetransdermal drug delivery system according to this invention, utilizinga rate-controlling membrane.

FIG. 4 is a graph showing transdermal flux across cadaver skin at 35° C.of buspirone with 0%, 5% and 10% poly-N-vinyl-2-pyrrolidone.

FIG. 5 is a graph showing transdermal flux across cadaver skin at 35° C.of 6% and 10% melatonin with 0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 6 is a graph showing transdermal flux across cadaver skin at 35° C.of 4% and 6% tacrine with 0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 7 is a graph showing transdermal flux across cadaver skin at 35° C.of 10% and 12% testosterone with 0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 8 is a graph showing transdermal flux across cadaver skin at 35° C.of 2% and 4% alprazolam with 0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 9 is a graph showing transdermal flux across cadaver skin at 35° C.of 2.5% gestodene with 0%, 15% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 10 is a graph showing transdermal flux of gestodene across cadaverskin at 35° C. of 2.5% gestodene and 2% ethinyl estradiol with 0% and20% poly-N-vinyl-2-pyrrolidone.

FIG. 11 is a graph showing transdermal flux of ethinyl estradiol acrosscadaver skin at 35° C. of 2% ethinyl estradiol with 0% and 20%poly-N-vinyl-2-pyrrolidone.

FIG. 12 is a graph showing transdermal flux of gestodene across cadaverskin at 35° C. of 2.5% gestodene and 2% ethinyl estradiol with 0% and20% poly-N-vinyl-2-pyrrolidone.

FIG. 13 is a graph showing transdermal flux of ethinyl estradiol acrosscadaver skin at 35° C. of 2.5% gestodene and 2% ethinyl estradiol with0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 14 is a bar graph showing the effect of poly-N-vinyl-2-pyrrolidoneon the transdermal flux across several cadaver skins of 2.5% gestodene.

FIG. 15 is a graph showing transdermal flux of gestodene across cadaverskin at 35° C. of 2.5% gestodene and 2% ethinyl estradiol with 0%, 25%and 30% glycerol monooleate and 0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 16 is a graph showing transdermal flux of gestodene across cadaverskin at 35° C. at 2.5% gestodene and 2% ethinyl estradiol with 0%, 25%and 30% glycerol monooleate and 0% and 20% poly-N-vinyl-2-pyrrolidone.

FIG. 17 is a graph showing the effect of poly-N-vinyl-2-pyrrolidone onthe wearability of a transdermal system having a cloth backing.

FIG. 18 is a graph showing the effect of poly-N-vinyl-2-pyrrolidone onthe wearability of a transdermal system having a medpar backing.

DESCRIPTION OF THE INVENTION

Examples of suitable transdermal delivery devices are illustrated inFIGS. 1, 2, and 3. The same reference numbers are used throughout thedifferent figures to designate the same or similar components. Thefigures are not drawn to scale.

In FIG. 1, a preferred embodiment of this invention, transdermaldelivery device 10, comprises a matrix reservoir 12 comprising drug, atherapeutically acceptable permeation enhancer and a poly-N-vinyl amide.

Reservoir matrix 12 is sandwiched between a backing layer 14 and anin-line contact adhesive layer 16. The backing layer 14 serves thepurpose of preventing passage of drug through the surface of the matrixdistant the skin, and also for providing support for the system, whereneeded.

The device 10 adheres to the surface of the skin 18 by means of theadhesive layer 16. The adhesive 16 may optionally contain enhancerand/or drug. The composition and thickness of adhesive layer 16 isselected such that the adhesive does not constitute a significantpermeation barrier to the passage of drug. A strippable release liner(not shown in FIG. 1) is normally provided along the exposed surface ofadhesive layer 16 and is removed prior to application of device 10 tothe skin 18. Preferably, the strippable liner is a siliconized polyesterfilm or fluorocarbon diacrylate film.

Because of the wide variation in skin permeability from individual andfrom site to site on the same body, it may be preferable that drug andthe permeation enhancer be administered from a rate-controlledtransdermal delivery device. Rate control can be obtained either througha rate-controlling membrane or adhesive, or through the other meansdisclosed in the patents noted above. Optionally, a rate-controllingmembrane (not shown) may be present between the reservoir matrix 12 andthe adhesive layer 16.

Alternatively, as shown in FIG. 2, transdermal therapeutic device 20 maybe attached to the skin or mucosa of a patient by means of an adhesiveoverlay 22. Device 20 is comprised of drug-, permeation enhancer- andpoly-N-vinyl amide-containing reservoir matrix 12. A backing layer 14 isprovided adjacent one surface of reservoir 12. Adhesive overlay 22maintains the device on the skin and may be fabricated together with, orprovided separately from, the remaining elements of the device. Withcertain formulations, the adhesive overlay 22 may be preferable to thein-line contact adhesive 16 as shown in FIG. 1. This is true, forexample, where the drug/enhancer reservoir contains a material (such as,for example, an oily surfactant permeation enhancer) that adverselyaffects the adhesive properties of the in-line contact adhesive layer16. Backing layer 14 is preferably slightly larger than reservoir matrix12, and in this manner prevents the materials in reservoir 12 fromadversely interacting with the adhesive in overlay 22. Optionally, arate-controlling membrane (not shown in FIG. 2) may be provided on theskin-proximal side of reservoir matrix 12. A strippable release liner 24is also provided with device 20 and is removed just prior to applicationof device 20 to the skin.

In FIG. 3, transdermal delivery device 30 comprises a drug-, permeationenhancer- and a poly-N-vinyl amide-containing reservoir matrix 12substantially as described with respect to FIG. 1. Permeation enhancerreservoir (“enhancer reservoir”) 26 comprises a permeation enhancer anda poly-N-vinyl amide dispersed throughout and is optionally containingthe drug. Enhancer reservoir 26 is preferably made from substantiallythe same matrix as is used to form drug reservoir matrix 12. Arate-controlling membrane 28 for controlling the release rate of thepermeation enhancer from enhancer reservoir 26 to drug reservoir matrix12 is placed between the two reservoirs. A rate-controlling membrane(not shown in FIG. 3) for controlling the release rate of the enhancerfrom drug reservoir matrix 12 to the skin may also optionally beutilized and would be present between adhesive 16 and reservoir matrix12.

Superimposed over the permeation enhancer reservoir 26 of device 30 is abacking 14. On the skin-proximal side of reservoir matrix 12 are anadhesive 16 and a strippable liner 24 that would be removed prior toapplication of the device 30 to the skin.

Suitable materials for the drug matrix include, without limitation,natural and synthetic rubbers or other polymeric materials, thickenedmineral oil, or petroleum jelly. A preferred embodiment according tothis invention is fabricated from an ethylene/vinyl acetate (EVA)copolymer of the type described in U.S. Pat. No. 4,144,317, incorporatedherein in its entirety by reference, preferably those having a vinylacetate content (VA) in the range of 9 to 60 weight percent and morepreferably 28% to 50% VA. Polyisobutylene/oil polymers containing from4-25% high molecular weight polyisobutylene and 20-80% low molecularweight polyisobutylene with the balance being an oil such as mineral oilor polybutenes may also be used as the matrix material.

The backing layer can be flexible or nonflexible, permeable orimpermeable to water vapor, or permeable or impermeable to permeationenhancers. It can have any combination of these characteristics. Thebacking, however, must be impermeable to drug. Suitable materialsinclude, without limitation, acrylonitrile, cellophane, celluloseacetate, cellulosics, ethylcellulose, ethylene vinyl alcohol, ethylenevinyl acetate, plasticized vinylacetate-vinylchloride copolymers,polyethylene terephthalate, some types of nylons, rayon, polyethylene,polypropylene, polyvinyl alcohol, polyvinyl chloride, metallizedpolyester films, polyvinylidene chloride, polyester, polycarbonate,polystyrene, polyurethane, aluminum foil, and multi-laminate films. Thebacking may be a multi-laminate film layer.

The adhesive materials suitable for the present invention include,without limitation, acrylic adhesives, polyisobutylene adhesives, andamine resistant adhesives, such as silicone adhesives. Adhesivesdisclosed in U.S. Pat. Nos. 3,797,494 and 4,031,894 are incorporatedherein by reference. Preferably, the adhesive is an acrylate adhesive.

The rate-controlling membrane may be fabricated from permeable,semipermeable or microporous materials that are known in the art tocontrol the rate of agents into and out of delivery devices. Suitablematerials include, but are not limited to, high density polyethylene,low density polyethylene, polyvinyl acetate, polypropylene and ethylenevinyl acetate copolymers.

This invention contemplates the use of materials other than thosespecifically disclosed herein, including those which may hereafterbecome known to the art to be capable of performing the necessaryfunctions.

When a constant drug delivery rate is desired, the drug is normallypresent in the matrix at a concentration in excess of saturation, theamount of excess being a function of the desired length of the drugdelivery period of the system. The drug may, however, be present at alevel below saturation without departing from this invention as long asdrug is continuously administered to the same skin or mucosa site in anamount and for a period of time sufficient to provide the desiredtherapeutic rate and delivery profile.

The permeation enhancer is dispersed through the matrix or matrices,preferably at a concentration sufficient to provide permeation-enhancingamounts of enhancer in the reservoir throughout the anticipatedadministration period.

In addition to a drug and a therapeutically acceptable permeationenhancer, the matrix may also contain dyes, pigments, inert fillers,diluents, antioxidants, antibacterials, stabilizers, vehicles,anesthetics, rubefacients, antipruritics, gelling agents, excipients andother conventional components of pharmaceutical products or transdermaldevices known to the art.

In a preferred embodiment of this invention, reservoir matrix 12comprises 30 to 70 weight percent polymer (preferably 28 to 50 percent),1 to 40 weight percent drug (preferably 5 to 25 weight percent), 1 to 50weight percent permeation enhancer (preferably 10 to 40 weight percent),and 5 to 40 weight percent poly-N-vinyl amide (preferably 10 to 25weight percent).

In a preferred embodiment of this invention, reservoir matrix 12comprises 30 to 70 weight percent ethylene vinyl acetate copolymerhaving a 9 to 60 percent vinyl acetate content (preferably 28 to 50percent), 1 to 40 weight percent drug (preferably 5 to 25 weightpercent), 1 to 50 weight percent permeation enhancer (preferably 10 to40 weight percent), and 5 to 40 weight percent poly-N-vinyl amide(preferably 10 to 25 weight percent), preferablypoly-N-vinyl-2-pyrrolidone.

In a preferred embodiment of this invention, reservoir matrix 12comprises 30 to 70 weight percent ethylene vinyl acetate copolymerhaving a 9 to 60 percent vinyl acetate content (preferably 28 to 50percent), 1 to 40 weight percent drug (preferably 5 to 25 weightpercent), 5 to 40 percent lactic ester of an alcohol (preferably 10 to30 weight percent), preferably lauryl lactate, 1 to 30 weight percentmonoglyceride or mixture of monoglycerides of a fatty acid (preferably 5to 25 weight percent), preferably glycerol monolaurate or glycerolmonooleate, and 5 to 40 weight percent poly-N-vinyl amide (preferably 10to 25 weight percent), preferably N-vinyl-2-pyrrolidone.

In a preferred embodiment of this invention, reservoir matrix 12comprises 30 to 70 weight percent ethylene vinyl acetate copolymerhaving a 9 to 60 percent vinyl acetate content (preferably 28 to 50percent), 1 to 40 weight percent drug (preferably 5 to 25 weightpercent), 1 to 30 weight percent monoglyceride or mixture ofmonoglycerides of a fatty acid (preferably 5 to 25 weight percent),preferably glycerol monolaurate or glycerol monooleate, and 5 to 40weight percent poly-N-vinyl amide (preferably 10 to 25 weight percent),preferably N-vinyl-2-pyrrolidone.

The devices of this invention can be designed to effectively deliverdrug for an extended time period of from several hours up to 7 days orlonger.

The administration rate of the drug through the skin should besufficient to minimize the size of the device. The size of the device ofthis invention can vary from 1 cm² to greater than 200 cm². A typicaldevice, however, will have a size within the range of 5-50 cm². Thetransdermal therapeutic devices of the present invention are prepared ina manner known in the art, such as by those procedures, for example,described in the transdermal device patents listed previously herein.

This invention finds particular usefulness both in enhancingpermeability across skin and in increasing the wearability, ie,improving the adhesion, of a transdermal device. It is also useful inenhancing flux across mucosa. Further, this invention is useful indelivery of both systemically and topically active drugs. According toour invention, the permeation-enhancing mixture and the drug to bedelivered are placed in drug- and permeation-enhancingmixture-transmitting relationship to the appropriate body surface, andmaintained in place for the desired period of time.

The method for the transdermal administration of a drug of thisinvention comprises administering a drug, in a therapeutically effectiveamount, to the area of skin over the time period and coadministering apermeation-enhancing mixture according to this invention to the area ofskin from a polymer matrix containing a poly-N-vinyl amide.

The method for increasing the transdermal flux of a drug from atransdermal device made according to this invention comprisesincorporating into a polymer matrix of a reservoir of a transdermaldevice, wherein the reservoir also contains a therapeutically effectiveamount of a drug to be administered and a permeation-enhancing mixture,an effective amount, of a poly-N-vinyl amide, preferably 5 to 40 weightpercent, most preferably 10 to 25 weight percent, wherein thepoly-N-vinyl amide is preferably poly-N-vinyl-2-pyrrolidone, andtransdermally administering the drug in accordance with the teachings ofthis invention.

The method for improving the adhesion of a transdermal device madeaccording to this invention comprises incorporating into a polymermatrix of a reservoir of a transdermal device, wherein the reservoiralso contains a therapeutically effective amount of a drug to beadministered and a permeation-enhancing mixture, an effective amount, ofa poly-N-vinyl amide, preferably 5 to 40 weight percent, most preferably10 to 25 weight percent, wherein the poly-N-vinyl amide is preferablypoly-N-vinyl-2-pyrrolidone, and transdermally administering the drug inaccordance with the teachings of this invention.

The method for improving the stability of a transdermal device madeaccording to this invention comprises incorporating into a polymermatrix of a reservoir of a transdermal device, wherein the reservoiralso contains a therapeutically effective amount of a drug to beadministered and a permeation-enhancing mixture, an effective amount, ofa poly-N-vinyl amide, preferably 5 to 40 weight percent, most preferably10 to 25 weight percent, wherein the poly-N-vinyl amide is preferablypoly-N-vinyl-2-pyrrolidone, and transdermally administering the drug inaccordance with the teachings of this invention.

It is believed that this invention has utility in connection with thedelivery of drugs within the broad class normally delivered through bodysurfaces and membranes, including skin. As used herein, the expressions“drug” and “agent” are used interchangeably and are intended to havetheir broadest interpretation as to any therapeutically active substancethat is delivered to a living organism to produce a desired, usuallybeneficial, effect. In general, this includes therapeutic agents in allof the major therapeutic areas, including, but not limited to, ACEinhibitors, adenohypophyseal hormones, adrenergic neuron blockingagents, adrenocortical steroids, inhibitors of the biosynthesis ofadrenocortical steroids, alpha-adrenergic agonists, alpha-adrenergicantagonists, selective alpha-two-adrenergic agonists, analgesics,antipyretics and anti-inflammatory agents, androgens, local anesthetics,general anesthetics, antiaddictive agents, antiandrogens, antiarrhythmicagents, antiasthmatic agents, anticholinergic agents, anticholinesteraseagents, anticoagulants, antidiabetic agents, antidiarrheal agents,antidiuretic, antiemetic and prokinetic agents, antiepileptic agents,antiestrogens, antifungal agents, antihypertensive agents, antimicrobialagents, antimigraine agents, antimuscarinic agents, antineoplasticagents, antiparasitic agents, antiparkinson's agents, antiplateletagents, antiprogestins, antithyroid agents, antitussives, antiviralagents, atypical antidepressants, azaspirodecanediones, barbiturates,benzodiazepines, benzothiadiazides, beta-adrenergic agonists,beta-adrenergic antagonists, selective beta-one-adrenergic antagonists,selective beta-two-adrenergic agonists, bile salts, agents affectingvolume and composition of body fluids, butyrophenones, agents affectingcalcification, calcium channel blockers, cardiovascular drugs,catecholamines and sympathomimetic drugs, cholinergic agonists,cholinesterase reactivators, dermatological agents,diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens,ganglionic blocking agents, ganglionic stimulating agents, hydantoins,agents for control of gastric acidity and treatment of peptic ulcers,hematopoietic agents, histamines, histamine antagonists,5-hydroxytryptamine antagonists, drugs for the treatment ofhyperlipoproteinemia, hypnotics and sedatives, immunosuppressive agents,laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscularblocking agents, organic nitrates, opioid analgesics and antagonists,pancreatic enzymes, phenothiazines, progestins, prostaglandins, agentsfor the treatment of psychiatric disorders, retinoids, sodium channelblockers, agents for spasticity and acute muscle spasms, succinimides,thioxanthenes, thrombolytic agents, thyroid agents, tricyclicantidepressants, inhibitors of tubular transport of organic compounds,drugs affecting uterine motility, vasodilators, vitamins and the like.

In operation, device 10 is applied to a relatively nonhairy area of theskin that is preferably substantially free of wrinkles, creases orfolds. Various locations on the torso, such as the flank or shoulder,provide suitable sites for the transdermal system. Once the device isplaced on the skin, it will begin administering drug to the wearer.

A certain amount of drug will bind to the skin, and it is accordinglypreferred that the skin-contacting layer of the device include thisamount of the agent as a loading dose.

Typically, the system is applied for 16 hours to 7 days. The systemapplication is easily adapted for various duration treatments, butgenerally 24 to 72 hours is the nominal duration for treatment of asingle dose.

As used herein, the term “therapeutically effective” amount or raterefers to the amount or rate of drug or active agent needed to effectthe desired therapeutic result. The amount of drug present in thetherapeutic device and required to achieve a therapeutically effectiveresult depends on many factors, such as the minimum necessary dosage ofdrug for the particular indication being treated; the solubility in thematrix and permeability through the matrix, of the adhesive layer and ofthe rate-controlling membrane, if present; and the period of time forwhich the device will be fixed to the skin. The minimum amount of drugis determined by the requirement that sufficient quantities of drug mustbe present in the device to maintain the desired rate of release overthe given period of application. The maximum amount for safety purposesis determined by the requirement that the quantity of drug presentcannot exceed a rate of release that reaches toxic levels.

As used herein, the term “skin permeation-enhancing” amount refers tothe amount of permeation enhancer needed to effect the desiredtherapeutic result. The amount of permeation enhancer present in thetherapeutic device and required to achieve a therapeutically effectiveresult depends on many factors, such as the minimum necessary dosage ofdrug for the particular indication being treated; the solubility of thedrug and permeation enhancer in the matrix and permeability through thematrix, of the adhesive layer and of the rate-controlling membrane, ifpresent; and the period of time for which the device will be fixed tothe skin. The minimum amount of permeation enhancer is determined by therequirement that sufficient quantities of permeation enhancer must bepresent in the device to maintain the desired rate of drug release overthe given period of application. The maximum amount for safety purposesis determined by the requirement that the quantity of permeationenhancer present cannot exceed a rate of release that causes irritationor causes the drug level to reach toxic levels.

As used herein, the term “flux enhancing amount” refers to the amount ofpoly-N-vinyl amide present in the therapeutic device required to producean improvement in transdermal fluxes, storage stability, or drugutilization of the device over an identical device containing nopoly-N-vinyl amide. The amount depends on the solubility of thepermeation enhancer in the poly-N-vinyl amide.

As used herein, the term “adhesion-improving amount” refers to theamount of poly-N-vinyl amide present in the therapeutic device requiredto produce an improvement in the wearability, storage stability or drugutilization of the device over an identical device containing nopoly-N-vinyl amide.

As used herein, the term “stability-improving amount” refers to theamount of poly-N-vinyl amide present in the therapeutic device requiredto is produce an improvement in the wearability, storage stability ordrug utilization of the device over an identical device containing nopoly-N-vinyl amide.

As used herein the term “therapeutically acceptable permeation enhancer”means a monoglyceride or mixture of monoglycerides of a fatty acid; adimethyl alkylamide; a sucrose ester or a mixture of sucrose esters of afatty acid; a lactic ester of an alcohol; a polyethylene glycol ester ofa fatty acid; a benzoic acid of a fatty acid ester; an alkyl laurate; adiethanolamide of a fatty acid; and the like, and combinations thereof.The presently preferred permeation enhancers of the present inventionare monoglyceride or mixture of monoglycerides of fatty acids and alactic ester of an alcohol, either alone or in combination. The mostpreferred permeation enhancers are glycerol monolaurate, glycerolmonooleate, and lauryl lactate, either alone or in combination.

As used herein the term “poly-N-vinyl amide” means a poly-N-vinyl amideor combination of poly-N-vinyl amide such aspoly-N-vinylmethylacetamide, poly-N-vinylethylacetamide,poly-N-vinylmethyl-isobutyramide, poly-N-vinyl-2-pyrrolidone,poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone,poly-N-vinyl-caprolactam, poly-N-vinyl-5-methyl-2-pyrrolidone,poly-N-vinyl-3-methyl-2-pyrrolidone, and the like. Preferably, thepoly-N-vinyl amide is poly-N-vinyl-2-pyrrolidone (more preferablyPolyplasdone XL®, Polyplasdone XL-10®, GAF) having a molecular weight of10,000 to 5,000,000 Daltons and a particle size from 0.1 to 1000 μm.

As used herein, the term “transdermal” delivery or application refers tothe delivery or application of drug by passage through skin, mucosaand/or other body surfaces by topical application.

As used herein, the term “substantial portion of the time period” meansat least 60% of the time period, preferably at least 90% of the timeperiod. Correlatively, the term “substantially constant” means avariation of less than ±20%, preferably less than ±10%, over asubstantial portion of the time period.

As used herein, the term “extended period of time” or “extended timeperiod” means at least 16 hours.

As used herein, the term “a monoglyceride or mixture of monoglyceridesof fatty acids” has a total monoesters content of at least 51%, wherethe monoesters are those with from six to twenty carbon atoms, such asglycerol monooleate, glycerol monolaurate and glycerol monolinoleate.

As used herein, the term “fatty acids” refers to fatty acids that aresaturated or unsaturated and straight or chained, and include, forexample, lauric acid, myristic acid, stearic acid, oleic acid, linoleicacid and palmitic acid.

As used herein, the term “dimethyl alkylamide” refers to an alkyl having1 to 18 carbon atoms, preferably eight to sixteen carbon atoms, such asdimethyl lauramide.

As used herein, the term “sucrose ester or a mixture of sucrose estersof a fatty acid” refers to a fatty acid having six to twenty carbonatoms, such as sucrose monococoate.

As used herein, the term “lactic ester of an alcohol” refers to analcohol having two to eighteen carbon atoms, such as lauryl lactate,ethyl lactate, cetyl lactate and myristyl lactate.

As used herein, the term “polyethylene glycol ester of a fatty acid”refers to a polyethylene glycol having an average molecular weight of 50to 1000 and a fatty acid having from six to twenty carbon atoms, such aspolyethylene glycol-200 monolaurate and polyethylene glycol-400monolaurate.

As used herein, the term “benzoic acid of a fatty acid ester” refers toa fatty acid having from eight to eighteen carbon atoms, such asisoestearyl benzoate.

As used herein, the term “alkyl laurate” refers to an alkyl having fromtwo to eight carbon atoms, such as ethyl laurate.

As used herein, the term “diethanolamide of a fatty acid” refers to anamide, such as lauramide diethanolamide or cocamide diethanolamide,formed by a condensation reaction between a fatty acid having eight toeighteen carbon atoms, preferably ten to sixteen carbon atoms, anddiethanolamine.

As used herein, the term “glycerol monooleate” refers to glycerolmonooleate itself or a mixture of glycerides wherein glycerol monooleateis present in the greatest amount.

As used herein, the term “glycerol monolaurate” refers to glycerolmonolaurate itself or a mixture of glycerides wherein glycerolmonolaurate is present in the greatest amount.

As used herein, the term “glycerol monolinoleate” refers to glycerolmonolinoleate itself or a mixture of glycerides wherein glycerolmonolinoleate is present in the greatest amount.

The following examples are offered to illustrate the practice of thepresent invention and are not intended to limit the invention in anymanner.

EXAMPLE 1

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 40 percent (“EVA 40”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 40 pellets fused. Buspirone and glycerol monooleate werethen added. The mixture was blended for approximately 20 minutes at54°-56° C. and 30 rpm. After blending, the mixture was quickly cooled to40°-45° C., and calendered to a 2.8-4.0 mil thick film. The compositionsof the reservoirs are given in Table

TABLE 1 Drug/Permeation Enhancer Reservoir Composition (weight percent)buspirone/glycerol monooleate/EVA 40 (20/20/60) buspirone/glycerolmonooleate/EVA 40/ N-vinyl-2-pyrrolidone (20/20/55/5) buspirone/glycerolmonooleate/EVA 40/ N-vinyl-2-pyrrolidone (20/20/50/10)

The film was then laminated to an acrylate contact adhesive (MSP041991P,3M) on one side and Medpar® backing (3M) on the opposite side. Thelaminate was then cut into circles using a stainless steel punch.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of epidermis that had been blotted dry just priorto use. The excess epidermis was wrapped around the device so that noneof the device edge was exposed to the receptor solution.

The device covered with epidermis was attached to the flat side of theTeflon holder of a release rate rod using nylon netting and nickel wire.The rods were reciprocated in a fixed volume of receptor solution(distilled water). The entire receptor solution was changed at eachsampling time. The temperature of the water bath was maintained at 35°C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for buspirone content by HPLC. The fluxes achieved for thedifferent systems are shown in FIG. 4. As can be seen from FIG. 4, thedrug fluxes for the systems containing 10% N-vinyl-2-pyrrolidone werehigher than the drug fluxes for the systems containing noN-vinyl-2-pyrrolidone.

EXAMPLE 2

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 40% (“EVA 40”, U.S.I.Chemicals, Illinois) and N-vinyl-2-pyrrolidone (Polyplasdone XL-10®,GAF), if present, in an internal mixer ((Bra Bender type mixer) untilthe EVA 40 pellets fused. Melatonin and glycerol monooleate were thenadded. The mixture was blended for approximately 20 minutes at 54-56° C.and 30 rpm. After blending, the mixture was quickly cooled to 40°-45°C., and calendered to a 4 mil thick film. The compositions of thereservoirs are given in Table 2.

TABLE 2 Drug/permeation Enhancer Reservoir Composition (weight percent)EVA 40/glycerol monooleate/melatonin (64/30/6) EVA 40/glycerolmonooleate/melatonin/N-vinyl-2-pyrrolidone (44/30/6/20) EVA 40/glycerolmonooleate/melatonin (60/30/10) EVA 40/glycerolmonooleate/melatonin/N-vinyl-2-pyrrolidone (40/30/10/20)

The films were then laminated to an acrylate contact adhesive (80912 CN396791, 3M) on one side and a nylon reinforced polyurethane backingNRU-100-c (80931) on the opposite side. The film were then punched into⅝″ diameter disks using a stainless steel punch and taped to preventedge release.

For each device tested, the adhesive were placed against the stratumcorneum side of a disc of epidermis that had been blotted dry prior touse. The excess epidermis was then wrapped around the device.

The device covered with epidermis was attached to the flat side of theteflon holder of a release rate rod using nylon netting and nickel wire.The rods were reciprocated in a fixed volume of receptor solution(distilled water). The entire receptor solution was changed at eachsampling time. The temperature of the water level was maintained at 35°C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for melatonin content by HPLC. The fluxes achieved for thedifferent systems are shown in FIG. 5. As can be seen from FIG. 5, thedrug fluxes for the systems containing 20% N-vinyl-2-pyrrolidone werehigher than the drug fluxes for the systems that contained noN-vinyl-2-pyrrolidone.

EXAMPLE 3

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content or 40% (“EVA 40”, U.S.Chemicals, Illinois) and N-vinyl-2-pyrrolidone (Polyplasdone XL-10®,GAF) if present, in an internal mixer (Bra Bender type mixer) until theEVA 40 pellets fused. Tacrine and glycerol monooleate were then added.The mixture was blended for approximately 20 minutes at 54-56° C. and 30rpm. After blending the mixture was quickly cooled to 40-45° C., andcalendered to 4 mil thick film. The compositions of the reservoirs aregiven in Table 3.

TABLE 3 Drug/Permeation Enhancer Reservoir Composition (weight percent)tacrine/glycerol monooleate/EVA 40 (4/30/66) tacrine/glycerolmonooleate/EVA 40/N-vinyl-2-pyrrolidone (4/30/46/20) tacrine/glycerolmonooleate/EVA 40 (6/30/64) tacrine/glycerol monooleate/EVA40/N-vinyl-2-pyrrolidone (6/30/44/20)

The films were laminated to an acrylate contact adhesive (80912 CN396791, 3M) on one side and a nylon reinforced polyurethane backing(NRU-100-c) (80931) on the opposite side. The films were then cut intocircles using a stainless steel punch and taped to prevent edge release.

For each device tested, the adhesive were placed against the stratumcorneum side of a disc of epidermis that had been blotted dry just priorto use. The excess epidermis was then wrapped around the device.

The device covered with epidermis was attached to the flat side of theteflon holder of a release rate rod using nylon netting and nickel wire.The rods were reciprocated in a fixed volume of receptor solution (0.05Mphosphate at pH 4). The entire receptor solution was changed at eachsampling time. The temperature of the water bath was maintained at 35°C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for tacrine content by HPLC. The fluxes achieved for thedifferent systems are shown in FIG. 6. As can be seen from FIG. 6, thedrug fluxes for the systems containing 20% N-vinyl-2-pyrrolidone werehigher than the drug fluxes for the systems that contained noN-vinyl-2-pyrrolidone.

EXAMPLE 4

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 40 percent (“EVA 40”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF) if present, in an internal mixer (Bra Bender type mixer)until the EVA 40 pellets fused. Testosterone and glycerol monooleatewere then added. The mixture was blended for approximately 20 minutes at54-56° C. at 30 rpm. After blending the mixture was quickly cooled to40-45° C., and calendered to a 4 mil thick film. The compositions of thereservoirs are given in Table 4.

TABLE 4 Drug/Permeation Enhancer Reservoir Composition (weight percent)testosterone/glycerol monooleate/EVA 40 (10/30/60) testosterone/glycerolmonooleate/EVA 40/N-vinyl-2- pyrrolidone (10/30/40/20)testosterone/glycerol monooleate/EVA 40 (12/30/58) testosterone/glycerolmonooleate/EVA 40/N-vinyl-2- pyrrolidone (12/30/38/20)

The films were then laminated to an acrylate contact adhesive (code80912, CN396791, 3M) on one side and a nylon reinforced polyurethanebacking NRU-100-c (code 80931) on the opposite side. The films were thencut into circles using a stainless steel punch and taped to prevent edgerelease.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of epidermis that had been blotted dry just priorto use. The excess epidermis was then wrapped around the device.

The device covered with epidermis was attached to the flat side of theTeflon holder of a release rate rod using nylon netting and nickel wire.The rods were reciprocated in a fixed volume of receptor solution (0.1%benzoic acid). The entire receptor solution was changed at each samplingtime. The temperature of the water bath was maintained at 35° C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for testosterone content by HPLC. The fluxes achieved forthe different systems are shown in FIG. 7. As can be seen from FIG. 7,the drug fluxes for the systems containing 20% N-vinyl pyrrolidone werehigher than the drug fluxes for the systems containing noN-vinyl-2-pyrrolidone.

EXAMPLE 5

The drug/permeation enhancer reservoir were prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 40 percent (“EVA 40”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 40 pellets fused. Alprazolam and glycerol monooleate werethen added. The mixture was blended for approximately 20 minutes at54-56° C. and 30 rpm. After blending, the mixture was quickly cooled to40-45° C. and calendered to a 4 mil thick film. The compositions of thereservoirs are given in Table 5.

TABLE 5 Drug/Permeation Enhancer Reservoir Composition (weight percent)alprazolam/glycerol monooleate/EVA 40 (2/30/68) alprazolam/glycerolmonooleate/EVA 40/N-vinyl-2-pyrrolidone (2/30/48/20) alprazolam/glycerolmonooleate/EVA 40 (4/30/66) alprazolam/glycerol monooleate/EVA40/N-vinyl-2-pyrrolidone (4/30/46/20)

The films were then laminated to an acrylate contact adhesive (80912 CN396791, 3M) on one side and a NRU-100-c (80931) backing on the oppositeside. The films were then cut into circles using a stainless steel punchand taped to prevent edge release.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of epidermis that had been blotted dry just priorto use. The excess epidermis was then wrapped around the device.

The device covered with epidermis was attached to the flat side of theTeflon holder of a release rate rod using nylon netting and nickel wire.The rods were reciprocated in a fixed volume of receptor solution (0.01M phosphate buffer at pH 6). The entire receptor solution was changed ateach sampling time. The temperature of the water bath was maintained at35° C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for alprazolam content by HPLC. The fluxes achieved forthe different systems are shown in FIG. 8.

EXAMPLE 6

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 33 percent (“EVA 33”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 33 pellets fused. Gestodene, ethinyl estradiol andglycerol monooleate were then added. The mixture was blended, andcalendered to a 4 mil thick film. The compositions of the reservoirs aregiven in Table 6.

TABLE 6 Drug/Permeation Enhancer Reservoir Composition (weight percent)ethinyl estradiol/gestodene/glycerol monooleate/EVA 33 (2/2.5/23.9/71.6)ethinyl estradiol/gestodene/glycerol monooleate/EVA33/N-vinyl-2-pyrrolidone (2/2.5/23.9/56.6/15) ethinylestradiol/gestodene/glycerol monooleate/EVA 33/N-vinyl-2-pyrrolidone(2/2.5/23.9/51.6/20)

This film was then laminated to an acrylate contact adhesive (147-123-4,Adhesive Research Co.) on one side and a nylon reinforced polyurethanebacking NRU-100-c® (code 80931) (Flexcon Co.) on the opposite side. Thefilm was then cut into circles and taped to prevent edge release.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of human epidermis that had been blotted dry justprior to use. The excess epidermis was wrapped around the device so thatnone of the device edge was exposed to the receptor solution. The devicecovered with epidermis was attached to the flat side of the Teflonholder of a release rod using nylon netting and nickel wire. The rodswere reciprocated in a fixed volume of receptor solution (distilledwater). The entire receptor solution was changed at each sampling time.The temperature of the receptor solution in the water bath wasmaintained at 35° C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for gestodene content by HPLC. The fluxes achieved for thedifferent systems are shown in FIG. 9. As can be seen from FIG. 9, thedrug fluxes for the systems containing N-vinyl-2-pyrrolidone were higherthan the drug fluxes for the systems that contained noN-vinyl-2-pyrrolidone.

EXAMPLE 7

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 33 percent (“EVA 33”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 33 pellets fused. Gestodene, ethinyl estradiol andglycerol monooleate were then added. The mixture was blended, andcalendered to a 4 mil thick film. The compositions of the reservoirs aregiven in Table 7.

TABLE 7 Drug/Permeation Enhancer Reservoir Composition (weight percent)ethinyl estradiol/gestodene/glycerol monooleate/EVA 33 (2/2/20/76)ethinyl estradiol/gestodene/glycerol monooleate/EVA33/N-vinyl-2-pyrrolidone (2/2/20/71/5)

This film was then laminated to an acrylic contact adhesive with arelease liner (80912, 3M) on one side and a nylon reinforcedpolyurethane backing NRU-100-c® (code 80931) (Flexcon Co.) on theopposite side. A ⅝″ diameter disc was punched from each film. The filmswere then observed.

In the composition without the N-vinyl-2-pyrrolidone, there was residueon the release liner. In the composition with the N-vinyl-2-pyrrolidone,there was no residue was on the release liner.

EXAMPLE 8

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 33 percent (“EVA 33”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 33 pellets fused. Gestodene, ethinyl estradiol andglycerol monooleate were then added. The mixture was blended, andcalendered to a 4 mil thick film. The compositions of the reservoirs aregiven in Table 8.

TABLE 8 Drug/Permeation Enhancer Reservoir Composition (weight percent)ethinyl estradiol/gestodene/glycerol monooleate/EVA 33 (2/2.5/19.3/76.2)ethinyl estradiol/gestodene/glycerol monooleate/EVA33/N-vinyl-2-pyrrolidone (2/2.5/19.3/61.2/15) ethinylestradiol/gestodene/glycerol monooleate/EVA 33/N-vinyl-2-pyrrolidone(2/2.5/19.3/51.2/25)

This film was then laminated to a nylon reinforced polyurethane backingNRU-100-c® (80931) (Flexcon Co.), such that on one side was a backingand on the other side was a release liner. A ⅝″ diameter disc waspunched from each film. The films were then observed.

The composition without the N-vinyl-2-pyrrolidone had residue on therelease liner and the reservoir surface was matted and oily. In thecompositions with the N-vinyl-2-pyrrolidone, no residue was on therelease liner and the reservoir surface was smooth with no oily texture.

EXAMPLE 9

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 28 percent (“EVA 28”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 28 pellets fused. Gestodene, ethinyl estradiol andglycerol monooleate were then added. The mixture was blended, andcalendered to a 4 mil thick film between two release liners. Thecompositions of the reservoirs are given in Table 9.

TABLE 9 Drug/Permeation Enhancer Reservoir Composition (weight percent)ethinyl estradiol/gestodene/glycerol monooleate/EVA 28 (2/5/27.9/65.1)ethinyl estradiol/gestodene/glycerol monooleate/EVA33/N-vinyl-2-pyrrolidone (2/5/27.9/45.1/20)

A ⅝″ diameter disc was punched from each film. The films were thenobserved. The composition without the N-vinyl-2-pyrrolidone had a lot ofresidue on both release liners. The compositions with theN-vinyl-2-pyrrolidone had residue on cut edges of one release liner.

EXAMPLE 10

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 28 percent (“EVA 28”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (PolyplasdoneXL-10®, GAF), if present, in an internal mixer (Bra Bender type mixer)until the EVA 28 pellets fused. Glycerol monooleate was then added. Themixture was blended, and calendered to a 4 mil thick film. Thecompositions of the reservoirs are given in Table 10.

TABLE 10 Drug/Permeation Enhancer Reservoir Composition (weight percent)glycerol monooleate/EVA 28 (20/80) glycerol monooleate/EVA33/N-vinyl-2-pyrrolidone (20/75/5)

This film was then laminated to an acrylate contact adhesive (80912, 3M)on one side and a nylon reinforced polyurethane backing NRU-100-c® (code80931) (Flexcon Co.) on the opposite side. In the composition that didnot contain N-vinyl-2-pyrrolidone, the reservoir had glycerol monooleateblooming out and the reservoir surface was oily. The layers did notlaminate together at room temperature, nor at a warm setting of a hotplate. When the setting was increased, the layers laminated together.The composition that contained N-vinyl-2-pyrrolidone the layerslaminated at room temperature and at an elevated temperature. No leakingof glycerol monooleate was observed.

EXAMPLES 11-12

The drug/permeation enhancer reservoirs were prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 28% (“EVA 28”, U.S.I.Chemicals, Illinois) or EVA 40 in the case of the control, andN-vinyl-2-pyrrolidone (Polyplasdone XL®-10, GAF), if present, in aninternal mixer (Bra Bender type mixer) until the EVA 28 or 40 pelletsfused. Gestodene, ethinyl estradiol and glycerol monooleate were thenadded. The mixture was blended for approximately 20 minutes at 54-56° C.and 30 rpm. After blending, the mixture was quickly cooled to 40-45° C.and calendered to a 4 mil thick film. The compositions of the reservoirsare given in Table 11.

TABLE 11 Drug/Permeation Enhancer Reservoir Composition (weight percent)Ethinyl estradiol/gestodene/glycerol monooleate/EVA 40 (2/2.5/30/35.5)Ethinyl estradiol/gestodene/glycol monooleate/EVA 40/N-vinyl-2-pyrrolidone (2/2.5/30/15.5/20)

The films were then laminated to an acrylate contact adhesive (80912,3M) on one side and a nylon reinforced polyurethane backing NRU-100-c®(code 80931) (Flexcon Co.) on the opposite side. The films were then cutinto circles and taped to prevent edge release.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of human epidermis that had been blotted dry justprior to use. The excess epidermis was then wrapped around the device.The device covered with epidermis was attached to the flat side of theteflon holder of a release rod using nylon netting and nickel wire. Therods were reciprocated in a fixed volume of receptor solution. Theentire receptor solution was changed at each sampling time. Thetemperature of the receptor solution in the water bath was maintained at35° C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for gestodene and ethinyl estradiol content. The fluxesachieved for the different systems and examples are shown in FIGS. 10-3,the gestodene fluxes are shown in FIGS. 10 and 12 and the ethinylestradiol fluxes are shown in FIGS. 11 and 13. As can be seen from FIGS.10-13 the drug fluxes for the systems containing N-vinyl-2-pyrrolidonewere higher than the drug fluxes for the systems containing noN-vinyl-2-pyrrolidone.

A grand summary showing the effect of N-vinyl-2-pyrrolidone on gestodenetransdermal flux of systems made according to the above descriptioncontaining 30% by weight glycerol monooleate, 2.5% by weight gestodene,2.0% by weight ethinyl estradiol, and 0 or 20% by weightN-vinyl-2-pyrrolidone in an EVA matrix is shown in FIG. 14.

EXAMPLE 13

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate having a vinyl acetate content of 33 percent (“EVA 33”,U.S.I. Chemicals, Illinois) and N-vinyl-2-pyrrolidone (Polyplasdone XL®and XL-10®, GAF), if present, in an internal mixer (Bra Bender typemixer) until the EVA 33 pellets fused. Gestodene, ethinyl estradiol andglycerol monooleate were then added. The mixture was blended andcalendered to a 4 mil thick film. The compositions of the reservoirs aregiven in Table 12.

TABLE 12 Drug/Permeation Enhancer Reservoir Composition (weight percent)EVA 40/glycerol monooleate/melatonin (64/30/6) ethinylestradiol/gestodene monooleate/ EVA 33/n-vinyl-2-pyrrolidone(2.0/2.5/25/70.5/0) ethinyl estradiol/gestodene/glycerol monooleate/ EVA33/N-vinyl-2-pyrrolidone (2.0/2.5/0/75.5/20) ethinylestradiol/gestodene/glycerol monooleate/ EVA 33/N-vinyl-2-pyrrolidone(2.0/2.5/0/95.5/0) ethinyl estradiol/gestodene/glycerol monooleate/ EVA33/N-vinyl-2-pyrrolidone (2.0/2.5/30/45.5/20) ethinylestradiol/gestodene/glycerol monooleate/ EVA 33/N-vinyl-2-pyrrolidone(2.0/2.5/30/45.5/20)

The films were then laminated to an acrylate contact adhesive (80912,3M) on one side and a nylon reinforced polyurethane backing NRU-100-c®(code 80931) (Flexcon Co.) on the opposite side. The films were then cutinto circles and taped to prevent edge release. The reservoircompositions were tested on two different skins.

For each device tested, the adhesive was placed against the stratumcornea side of a disc of human epidermis that had been blotted dry justprior to use. The excess epidermis was then wrapped around the device.The device covered with epidermis was attached to the flat side of theTeflon holder of a release rod using nylon netting and nickel wire. Therods were reciprocated in a fixed volume of receptor solution. Theentire receptor solution changed at each sampling time. The temperatureof the receptor solution in the water bath was maintained at 35° C.

The receptor solutions were stored in capped vials at room temperatureuntil assayed for gestodene content by HPLC. The fluxes achieved for thedifferent systems are shown in FIGS. 15 and 16. As can be seen fromFIGS. 15 and 16, the drug fluxes for the systems containing bothN-vinyl-2-pyrrolidone and permeation enhancer, glycerol monooleate, werehigher than the drug fluxes for the systems containing only permeationenhancer or only N-vinyl-2-pyrrolidone, thus indicating that thecombination of permeation enhancer with a n-poly-vinyl amide producesmore than an additive effect.

EXAMPLE 14

The laminate reservoir was prepared by mixing ethylene vinyl acetatehaving a vinyl acetate content at 33 percent (“EVA 33”, U.S.I Chemicals,Illinois) and N-vinyl-2-pyrrolidone (Polyplasdone XL-10®, GAF), ifpresent, in an internal mixer (Bra Bender type mixer) until the EVA 40pellets fused. Glycerol monooleate was then added. The mixture wasblended and calendered to a 4 mil thick film. The compositions of thereservoirs are given in Table 13.

TABLE 13 Laminate Reservoir Composition (weight percent) EVA 33/glycerolmonooleate/N-vinyl-2-pyrrolidone (50/30/20) EVA 40/glycerol monooleate(70/30)

The films were then laminated to an acrylate contact adhesive (80912,3M) on one side and a nylon reinforced polyurethane backing NRU-100-c®(code 80931) (Flexcon Co.) on the opposite side. A {fraction (13/16)}″diameter disc was punched from each film and the laminates were used ina seven day wear study. Table 14 depicts the results of the wear study.

TABLE 14 Days Worn 0% PVPXL-10 20% PVPXL-10 0-1 1-2 2-3 3-4 4-5  4  45-6 5, 5 6-7 removed 28 42 total days worn¹ 42 46 # fall off 0-7 days² 3  1 ²The maximum number of possible days worn is 49. ³The maximumnumber of possible fall offs is 7.

As Table 14 indicates, the addition of N-vinyl-2-pyrrolidone into thedrug reservoir improves the wearability of a system.

EXAMPLE 15

The laminate reservoir was prepared by mixing ethylene vinyl acetatehaving a vinyl acetate content of 40 percent (“EVA 40”, U.S.I.Chemicals, Illinois) and N-vinyl-2-pyrrolidone (Polyplasdone XL-10®,GAF), if present, or Cabosil (Cabot), if present, in an internal mixer(Bra Bender type mixer) until the EVA 40 pellets fused. Glycerolmonolaurate and lauryl lactate were then added. The mixture was blendedand calendered to a 4 mil thick film. The compositions of the reservoirsare given in Table 15.

TABLE 15 Laminate Reservoir Composition Inline Backing (weight percent)Adhesive Sontara EVA 40/GML/LL(60/25/15) 3M Sontara EVA40/GML/LL/Cabosil(55/25/15/5) 3M Sontara EVA40/GML/LL/Cabosil(50/25/15/10) 3M Sontara EVA 40/GML/LL/N-vinyl-2- 3Mpyrrolidone(50/25/15/10) Sontara EVA 40/GML/LL/N-vinyl-2- 3Mpyrrolidone(40/25/15/20)

The films were then laminated to an acrylate content adhesive with arelease liner on one side(80912, 3M)and a Sontara (80632B CN 352790)backing on the opposite side.

Table 16 depicts the summary of wearing times for this example. As Table16 indicates the total days worn for the systems containingN-vinyl-2-pyrrolidone is greater than for those containing noN-vinyl-2-pyrrolidone.

TABLE 16 Summary of Wearing Times Days No 5% 10% 10% 20% Worn AdditiveCabosil Cabosil PVPXL-10 PVPXL-10 0-1 .6* .9* .5 .4* .9* .4* .9* .9* 1-21.8 1.5 2-3 2.9* 3-4 3.0 3.0 4-5 4.5 4.9* 5-6 5.0 5.8* 6-7 6.1 removed¹77.0 63.0 70.0 84.0 77.0 total days 83.5 71.1 75.8 91.0 90.6 worn² #fall offs 2 4 3 1 1 0-3 days³ # fall offs 3 5 4 2 3 0-7 days³ *indicatessystems that fell while exercising or while bathing ¹The value is equalto the number of individuals in which the system was removed times sevendays. ²The maximum number of possible days worn is 98. ³The maximumnumber of possible fall offs is 14.

EXAMPLE 16

The laminate reservoir was prepared by mixing ethylene vinyl acetatehaving a vinyl acetate content of 40 percent (“EVA 40”, U.S.I.Chemicals, Illinois) and N-vinyl-2-pyrrolidone (Polyplasdone XL-10®,GAF), if present, in an internal mixer (Bra Bender type mixer) until theEVA 40 pellets fused. Glycerol monolaurate and lauryl lactate were thenadded. The mixture was blended and calendered to a 4.0 mil thick film.The films were then laminated to an acrylate contact adhesive with arelease liner on one side (80912, 3M) and either a medpar or clothbacking Sontara (80632B Cn 352790) or on the opposite side. Thecompositions of the reservoirs are given in Table 17.

TABLE 17 Backing Reservoir Formulation (weight percent) Cloth EVA40/GML/LL(60/25/15) Cloth EVA 40/GML/LL/N-vinyl-2-pyrrolidone(50/25/15/10) Cloth EVA 40/GML/LL/N-vinyl-2-pyrrolidone(40/25/15/20) Medpar EVA 40/GML/LL(60/25/15) Medpar EVA40/GML/LL/N-vinyl-2- pyrrolidone(50/25/15/10) Medpar EVA40/GML/LL/N-vinyl-2- pyrrolidone(40/25/15/20)

The systems were then used in a seven day wear study. The results of thewear study are depicted in Table 18 and FIGS. 15 and 16.

TABLE 18 Systems Remaining on at Time Given Cloth Cloth Cloth Days 0%10% 20% MEDPAR MEDPAR MEDPAR worn PVP PVP PVP 0% PVP 10% PVP 20% PVP  0days 12  13  13  13  13  13  0-1 days 8 12  13  2 4 5 1-2 days 7 12  12 1 1 3 2-3 days 7 12  12  0 1 3 3-4 days 6 12  11  0 1 3 4-5 days 5 10 10  0 1 2 5-6 days 4 9 9 0 1 1 6-7 days 2 8 9 0 1 1 7-8 days 2 8 9 0 1 0removed 2 8 9 0 1 0

As is seen in FIGS. 15 and 16, and in Table 18, the systems containingN-vinyl-2-pyrrolidone displayed a higher patch survival rate, ie, thepatches stayed on the subject longer than those without theN-vinyl-2-pyrrolidone.

While the invention has been described with reference to specificembodiments, it will be apparent to those skilled in the art that manyalternatives, modifications and variations may be needed. Accordingly,it is intended to embrace all such alternatives, modifications, andvariations that may fall within the spirit and scope at the appendedclaims.

What is claimed is:
 1. A method for enhancing the transdermal flux of adrug from a transdermal device comprising: (a) incorporating into areservoir of a transdermal 5-25 wt % poly-N-vinyl-2-pyrrolidone, whereinsaid device comprises: (i) a reservoir containing an estrogen and aprogestin and a permeation enhancing amount of a monoglyceride or amixture of monoglycerides of a fatty acid with a total monoesterscontent of at least 51% or a lactic ester of an alcohol, separately orin combination, said estrogen, progestin, and permeation enhancer beingdispersed and/or dissolved in a polymeric carrier; (ii) a backing layeradjacent the skin distal surface of the device; (iii) means formaintaining the reservoir in drug and permeation enhancer transmittingrelation with the skin; and (b) placing the device onto the skin of aperson.
 2. A method for enhancing adhesion of a transdermal devicecomprising: (a) incorporating into a reservoir of a transdermal 5-25 wt% poly-N-vinyl-2-pyrrolidone, wherein said device comprises: (i) areservoir containing an estrogen and a progestin and a permeationenhancing amount of a monoglyceride or a mixture of monoglycerides of afatty acid with a total monoesters content of at least 51% or a lacticester of an alcohol, separately or in combination, said estrogen,progestin, and permeation enhancer being dispersed and/or dissolved in apolymeric carrier; (ii) a backing layer adjacent the skin distal surfaceof the device; (iii) means for maintaining the reservoir in drug andpermeation enhancer transmitting relation with the skin; and (b) placingthe device onto the skin of a person.
 3. A method for enhancing thestability of a transdermal device comprising: (a) incorporating into areservoir of a transdermal 5-25 wt % poly-N-vinyl-2-pyrrolidone, whereinsaid device comprises: (i) a reservoir containing an estrogen and aprogestin and a permeation enhancing amount of a monoglyceride or amixture of monoglycerides of a fatty acid with a total monoesterscontent of at least 51% or a lactic ester of an alcohol, separately orin combination, said estrogen, progestin, and permeation enhancer beingdispersed and/or dissolved in a polymeric carrier; (ii) a backing layeradjacent the skin distal surface of the device; and (iii) means formaintaining the reservoir in drug and permeation enhancer transmittingrelation with the skin.
 4. A method according to any of claims 1-3wherein the reservoir contains 1-50 wt % of a lactic ester of analcohol.
 5. A method according to claim 4 wherein the lactic ester islauryl lactate.
 6. A method according to any of claims 1-3 or 5 whereinthe polymeric carrier comprises a pressure sensitive adhesive thatfunctions as the means for maintaining the device in drug and permeationenhancer transmitting relation with the skin.